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BACKGROUND: Conventional ECG-based algorithms could contribute to sudden cardiac death (SCD) risk stratification but demonstrate moderate predictive capabilities. Deep learning (DL) models use the entire digital signal and could potentially improve predictive power. We aimed to train and validate a 12 lead ECG-based DL algorithm for SCD risk assessment. METHODS: Out-of-hospital SCD cases were prospectively ascertained in the Portland, Oregon, metro area. A total of 1,827 pre- cardiac arrest 12 lead ECGs from 1,796 SCD cases were retrospectively collected and analyzed to develop an ECG-based DL model. External validation was performed in 714 ECGs from 714 SCD cases from Ventura County, CA. Two separate control group samples were obtained from 1342 ECGs taken from 1325 individuals of which at least 50% had established coronary artery disease. The DL model was compared with a previously validated conventional 6 variable ECG risk model. RESULTS: The DL model achieves an AUROC of 0.889 (95% CI 0.861-0.917) for the detection of SCD cases vs. controls in the internal held-out test dataset, and is successfully validated in external SCD cases with an AUROC of 0.820 (0.794-0.847). The DL model performs significantly better than the conventional ECG model that achieves an AUROC of 0.712 (0.668-0.756) in the internal and 0.743 (0.711-0.775) in the external cohort. CONCLUSIONS: An ECG-based DL model distinguishes SCD cases from controls with improved accuracy and performs better than a conventional ECG risk model. Further detailed investigation is warranted to evaluate how the DL model could contribute to improved SCD risk stratification.
Sudden cardiac death (SCD) occurs when there are problems with the electrical activity within the heart. It is a common cause of death throughout the world so it would be beneficial to be able to easily identify individuals that are at high risk of SCD. Electrocardiograms are a cheap and widely available way to measure electrical activity in the heart. We developed a computational method that can use electrocardiograms to determine whether a person is at increased risk of having a SCD. Our computational method could allow clinicians to screen large numbers of people and identify those at a higher risk of SCD. This could enable regular monitoring of these people and might enable SCDs to be prevented in some individuals.
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BACKGROUND AND AIMS: Electrocardiogram (ECG) abnormalities have been evaluated as static risk markers for sudden cardiac death (SCD), but the potential importance of dynamic ECG remodelling has not been investigated. In this study, the nature and prevalence of dynamic ECG remodelling were studied among individuals who eventually suffered SCD. METHODS: The study population was drawn from two prospective community-based SCD studies in Oregon (2002, discovery cohort) and California, USA (2015, validation cohort). For this present sub-study, 231 discovery cases (2015-17) and 203 validation cases (2015-21) with ≥2 archived pre-SCD ECGs were ascertained and were matched to 234 discovery and 203 validation controls based on age, sex, and duration between the ECGs. Dynamic ECG remodelling was measured as progression of a previously validated cumulative six-variable ECG electrical risk score. RESULTS: Oregon SCD cases displayed greater electrical risk score increase over time vs. controls [+1.06 (95% confidence interval +0.89 to +1.24) vs. -0.05 (-0.21 to +0.11); P < .001]. These findings were successfully replicated in California [+0.87 (+0.7 to +1.04) vs. -0.11 (-0.27 to 0.05); P < .001]. In multivariable models, abnormal dynamic ECG remodelling improved SCD prediction over baseline ECG, demographics, and clinical SCD risk factors in both Oregon [area under the receiver operating characteristic curve 0.770 (95% confidence interval 0.727-0.812) increased to area under the receiver operating characteristic curve 0.869 (95% confidence interval 0.837-0.902)] and California cohorts. CONCLUSIONS: Dynamic ECG remodelling improved SCD risk prediction beyond clinical factors combined with the static ECG, with successful validation in a geographically distinct population. These findings introduce a novel concept of SCD dynamic risk and warrant further detailed investigation.
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Arritmias Cardíacas , Muerte Súbita Cardíaca , Humanos , Estudios Prospectivos , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Arritmias Cardíacas/complicaciones , Factores de Riesgo , Electrocardiografía/efectos adversosRESUMEN
Background Out-of-hospital sudden cardiac arrest (SCA) is a leading cause of mortality, making prevention of SCA a public health priority. No studies have evaluated predictors of SCA risk among Hispanic or Latino individuals in the United States. Methods and Results In this case-control study, adult SCA cases ages 18-85 (n=1,468) were ascertained in the ongoing Ventura Prediction of Sudden Death in Multi-Ethnic Communities (PRESTO) study (2015-2021) in Ventura County, California. Control subjects were selected from 3033 Hispanic or Latino participants who completed Visit 2 examinations (2014-2017) at the San Diego site of the HCHS/SOL (Hispanic Community Health Survey/Study of Latinos). We used logistic regression to evaluate the association of clinical factors with SCA. Among Hispanic or Latino SCA cases (n=295) and frequency-matched HCHS/SOL controls (n=590) (70.2% men with mean age 63.4 and 61.2 years, respectively), the following clinical variables were associated with SCA in models adjusted for age, sex, and other clinical variables: chronic kidney disease (odds ratio [OR], 7.3 [95% CI, 3.8-14.3]), heavy drinking (OR, 4.5 [95% CI, 2.3-9.0]), stroke (OR, 3.1 [95% CI, 1.2-8.0]), atrial fibrillation (OR, 3.7 [95% CI, 1.7-7.9]), coronary artery disease (OR, 2.9 [95% CI, 1.5-5.9]), heart failure (OR, 2.5 [95% CI, 1.2-5.1]), and diabetes (OR, 1.5 [95% CI, 1.0-2.3]). Conclusions In this first population-based study, to our knowledge, of SCA risk predictors among Hispanic or Latino adults, chronic kidney disease was the strongest risk factor for SCA, and established cardiovascular disease was also important. Early identification and management of chronic kidney disease may reduce SCA risk among Hispanic or Latino individuals, in addition to prevention and treatment of cardiovascular disease.
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Muerte Súbita Cardíaca , Paro Cardíaco , Hispánicos o Latinos , Femenino , Humanos , Masculino , California/epidemiología , Estudios de Casos y Controles , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etnología , Muerte Súbita Cardíaca/etiología , Insuficiencia Renal Crónica/complicaciones , Factores de Riesgo , Estados Unidos , Paro Cardíaco/epidemiología , Paro Cardíaco/etnología , Paro Cardíaco/etiología , Persona de Mediana EdadRESUMEN
BACKGROUND: Sudden cardiac arrest is a global public health problem with a mortality rate of more than 90%. Prearrest warning symptoms could be harnessed using digital technology to potentially improve survival outcomes. We aimed to estimate the strength of association between symptoms and imminent sudden cardiac arrest. METHODS: We conducted a case-control study of individuals with sudden cardiac arrest and participants without sudden cardiac arrest who had similar symptoms identified from two US community-based studies of patients with sudden cardiac arrest in California state, USA (discovery population; the Ventura Prediction of Sudden Death in Multi-Ethnic Communities [PRESTO] study), and Oregon state, USA (replication population; the Oregon Sudden Unexpected Death Study [SUDS]). Participant data were obtained from emergency medical services reports for people aged 18-85 years with witnessed sudden cardiac arrest (between Feb 1, 2015, and Jan 31, 2021) and an inclusion symptom. Data were also obtained from corresponding control populations without sudden cardiac arrest who were attended by emergency medical services for similar symptoms (between Jan 1 and Dec 31, 2019). We evaluated the association of symptoms with sudden cardiac arrest in the discovery population and validated our results in the replication population by use of logistic regression models. FINDINGS: We identified 1672 individuals with sudden cardiac arrest from the PRESTO study, of whom 411 patients (mean age 65·7 [SD 12·4] years; 125 women and 286 men) were included in the analysis for the discovery population. From a total of 76â734 calls to emergency medical services, 1171 patients (mean age 61·8 [SD 17·3] years; 643 women, 514 men, and 14 participants without data for sex) were included in the control group. Patients with sudden cardiac arrest were more likely to have dyspnoea (168 [41%] of 411 vs 262 [22%] of 1171; p<0·0001), chest pain (136 [33%] vs 296 [25%]; p=0·0022), diaphoresis (50 [12%] vs 90 [8%]; p=0·0059), and seizure-like activity (43 [11%] vs 77 [7%], p=0·011). Symptom frequencies and patterns differed significantly by sex. Among men, chest pain (odds ratio [OR] 2·2, 95% CI 1·6-3·0), dyspnoea (2·2, 1·6-3·0), and diaphoresis (1·7, 1·1-2·7) were significantly associated with sudden cardiac arrest, whereas among women, only dyspnoea was significantly associated with sudden cardiac arrest (2·9, 1·9-4·3). 427 patients with sudden cardiac arrest (mean age 62·2 [SD 13·5]; 122 women and 305 men) were included in the analysis for the replication population and 1238 patients (mean age 59·3 [16·5] years; 689 women, 548 men, and one participant missing data for sex) were included in the control group. Findings were mostly consistent in the replication population; however, notable differences included that, among men, diaphoresis was not associated with sudden cardiac arrest and chest pain was associated with sudden cardiac arrest only in the sex-stratified multivariable analysis. INTERPRETATION: The prevalence of warning symptoms was sex-specific and differed significantly between patients with sudden cardiac arrest and controls. Warning symptoms hold promise for prediction of imminent sudden cardiac arrest but might need to be augmented with additional features to maximise predictive power. FUNDING: US National Heart Lung and Blood Institute.
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Paro Cardíaco , Masculino , Humanos , Femenino , Anciano , Persona de Mediana Edad , Estudios de Casos y Controles , Paro Cardíaco/epidemiología , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Dolor en el Pecho , DisneaAsunto(s)
Muerte Súbita Cardíaca , Paro Cardíaco , Humanos , Estudios Prospectivos , Paro Cardíaco/genéticaRESUMEN
BACKGROUND: Early during the coronavirus disease 2019 (COVID-19) pandemic, higher sudden cardiac arrest (SCA) incidence and lower survival rates were reported. However, ongoing effects on SCA during the evolving pandemic have not been evaluated. OBJECTIVE: The purpose of this study was to assess the impact of COVID-19 on SCA during 2 years of the pandemic. METHODS: In a prospective study of Ventura County, California (2020 population 843,843; 44.1% Hispanic), we compared SCA incidence and outcomes during the first 2 years of the COVID-19 pandemic to the prior 4 years. RESULTS: Of 2222 out-of-hospital SCA cases identified, 907 occurred during the pandemic (March 2020 to February 2022) and 1315 occurred prepandemic (March 2016 to February 2020). Overall age-standardized annual SCA incidence increased from 39 per 100,000 (95% confidence [CI] 37-41) prepandemic to 54 per 100,000 (95% CI 50-57; P <.001) during the pandemic. Among Hispanics, incidence increased by 77%, from 38 per 100,000 (95% CI 34-43) to 68 per 100,000 (95% CI 60-76; P <.001). Among non-Hispanics, incidence increased by 26%, from 39 per 100,000 (95% CI 37-42; P <.001) to 50 per 100,000 (95% CI 46-54). SCA incidence rates closely tracked COVID-19 infection rates. During the pandemic, SCA survival was significantly reduced (15% to 10%; P <.001), and Hispanics were less likely than non-Hispanics to receive bystander cardiopulmonary resuscitation (45% vs 55%; P = .005) and to present with shockable rhythm (15% vs 24%; P = .003). CONCLUSION: Overall SCA rates remained consistently higher and survival outcomes consistently lower, with exaggerated effects during COVID infection peaks. This longer evaluation uncovered higher increases in SCA incidence among Hispanics, with worse resuscitation profiles. Potential ethnicity-specific barriers to acute SCA care warrant urgent evaluation and intervention.
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COVID-19 , Reanimación Cardiopulmonar , Paro Cardíaco Extrahospitalario , Humanos , Pandemias , Estudios Prospectivos , COVID-19/epidemiología , COVID-19/complicaciones , Muerte Súbita Cardíaca/epidemiología , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Paro Cardíaco Extrahospitalario/epidemiología , Paro Cardíaco Extrahospitalario/etiología , Paro Cardíaco Extrahospitalario/terapia , América del NorteRESUMEN
BACKGROUND: The identification of circulating biomarkers specific for sudden cardiac arrest (SCA) could enhance risk prediction. Of particular interest are biomarkers specific to SCA, independent of coronary artery disease (CAD). OBJECTIVE: The purpose of this study was to identify biomarkers of SCA obtained close to the SCA event. METHODS: Twenty cases (survivors of SCA) and 40 age- and sex-matched controls were compared, with a replication analysis of 29 cases matched to 57 controls. A secondary analysis compared 20 SCA cases to 20 controls with CAD. Blood samples were obtained from SCA survivors at a median of 11 months after the SCA event. Proteins were analyzed on a mass spectrometer using data-independent acquisition; a subset of cytokines were analyzed using immunoassays; and 1153 lipids (13 classes) were analyzed. A false discovery rate P value of <.05 identified associated proteins. RESULTS: Patients had a mean age of 58 years (range 25-87 years), and 70% were male. A total of 26 protein biomarkers associated with SCA when cases were compared with controls, of which 20 differentiated SCA from CAD. The replication analysis identified 8 of 26 biomarkers, of which 6 were not overlapping with CAD. The top identified biological processes involved the extracellular matrix, coagulation cascades, and platelet activation. Lipids in the lysophosphatidylcholine class were implicated in SCA through the CAD pathway. CONCLUSION: We identified a panel of novel blood biomarkers specifically associated with SCA, including several that may be involved outside the CAD pathway. These biomarkers could have mechanistic significance and the potential to enhance clinical prediction of SCA.
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Enfermedad de la Arteria Coronaria , Muerte Súbita Cardíaca , Humanos , Masculino , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Enfermedad de la Arteria Coronaria/complicaciones , Biomarcadores , Lípidos , Factores de RiesgoRESUMEN
Background: Out-of-hospital sudden cardiac arrest (SCA) is a major public health problem with mortality >90%, and incidence has increased during the COVID-19 pandemic. Information regarding ethnicity-specific effects on SCA incidence and survival is lacking. Methods: In a prospective, population-based study of Ventura County, CA residents (2020 Pop. 843,843; 44.1% Hispanic), we compared SCA incidence and outcomes during the first two years of the COVID-19 pandemic to the prior four years, overall and by ethnicity (Hispanic vs non-Hispanic). Findings: Of 2,222 OHCA cases identified, 907 occurred during the pandemic (March 2020 - Feb 2022) and 1315 occurred pre-pandemic (March 2016 - Feb 2020). Overall age-standardized annual SCA incidence increased from 38.9/100,000 [95% CI 36.8-41.0] pre-pandemic to 53.8/100,00 [95% CI 50.3 - 57.3, p<0.001] during the pandemic. Among Hispanics, incidence increased by 77%, from 38.2/100,00 [95% CI 33.8-42.5] to 67.7/100,00 [95% CI 59.5- 75.8, p<0.001]. Among non-Hispanics, incidence increased by 26% from 39.4/100,000 [95% CI 36.9-41.9, p<0.001] to 49.8/100,00 [95% CI 45.8-53.8]. SCA incidence rates closely tracked COVID-19 infection rates. During the pandemic, SCA survival was significantly reduced (15.3% to 10.0%, p<0.001) and Hispanics were less likely than non-Hispanics to have bystander CPR (44.6% vs. 54.7%, p=0.005) and shockable rhythm (15.3% vs. 24.1%, p=0.003). Interpretation: Hispanic residents experienced higher SCA rates during the pandemic with less favorable resuscitation profiles. These findings implicate potential ethnicity-specific barriers to acute care and represent an urgent call to action at the community and health-system levels. Funding: National Heart Lung and Blood Institute Grants R01HL145675 and R01HL147358.
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Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated (ATM) and Aprataxin (APTX), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal's first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm, we demonstrate that Small Molecule Read-Through (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic.
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Ataxia Telangiectasia/genética , Atrofia/fisiopatología , Cerebelo/patología , Codón sin Sentido/genética , Células de Purkinje/metabolismo , Animales , Ataxia Telangiectasia/fisiopatología , Atrofia/genética , Modelos Animales de Enfermedad , Femenino , Masculino , RatonesRESUMEN
AIMS: The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing. METHODS AND RESULTS: Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033). CONCLUSIONS: Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.
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Cardiomiopatía Dilatada , Insuficiencia Cardíaca , Miocardio , Adulto , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Proteínas Portadoras/genética , Conectina/genética , Desmoplaquinas/genética , Femenino , Pruebas Genéticas , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/genética , Humanos , Masculino , Persona de Mediana Edad , Miocardio/ultraestructura , Miofibrillas/patología , Sarcómeros/genética , Sarcómeros/patologíaRESUMEN
Importance: Sudden cardiac arrest (SCA) is a major public health problem. Owing to a lack of population-based studies in multiracial/multiethnic communities, little information is available regarding race/ethnicity-specific epidemiologic factors of SCA. Objective: To evaluate the association of race/ethnicity with burden, outcomes, and clinical profile of individuals experiencing SCA. Design, Setting, and Participants: A 5-year prospective, population-based cohort study of out-of-hospital SCA was conducted from February 1, 2015, to January 31, 2020, among residents of Ventura County, California (2018 population, 848â¯112: non-Hispanic White [White], 45.8%; Hispanic/Latino [Hispanic], 42.4%; Asian, 7.3%; and Black, 1.7% individuals). All individuals with out-of-hospital SCA of likely cardiac cause and resuscitation attempted by emergency medical services were included. Exposures: Data on circumstances and outcomes of SCA from prehospital emergency medical services records and data on demographics and pre-SCA clinical history from detailed archived medical records, death certificates, and autopsies. Main Outcomes and Measures: Annual age-adjusted SCA incidence by race and ethnicity and SCA circumstances and outcomes by ethnicity. Clinical profile (cardiovascular risk factors, comorbidity burden, and cardiac history) by ethnicity, overall, and stratified by sex. Results: A total of 1624 patients with SCA were identified (1059 [65.2%] men; mean [SD] age, 70.9 [16.1] years). Race/ethnicity data were available for 1542 (95.0%) individuals, of whom 1022 (66.3%) were White, 381 (24.7%) were Hispanic, 86 (5.6%) were Asian, 31 (2.0%) were Black, and 22 (1.4%) were other race/ethnicity. Annual age-adjusted SCA rates per 100â¯000 residents of Ventura County were similar in White (37.5; 95% CI, 35.2-39.9), Hispanic (37.6; 95% CI, 33.7-41.5; P = .97 vs White), and Black (48.0; 95% CI, 30.8-65.2; P = .18 vs White) individuals, and lower in the Asian population (25.5; 95% CI, 20.1-30.9; P = .006 vs White). Survival to hospital discharge following SCA was similar in the Asian (11.8%), Hispanic (13.9%), and non-Hispanic White (13.0%) (P = .69) populations. Compared with White individuals, Hispanic and Asian individuals were more likely to have hypertension (White, 614 [76.3%]; Hispanic, 239 [79.1%]; Asian, 57 [89.1%]), diabetes (White, 287 [35.7%]; Hispanic, 178 [58.9%]; Asian, 37 [57.8%]), and chronic kidney disease (White, 231 [29.0%]; Hispanic, 123 [40.7%]; Asian, 33 [51.6%]) before SCA. Hispanic individuals were also more likely than White individuals to have hyperlipidemia (White, 380 [47.2%]; Hispanic, 165 [54.6%]) and history of stroke (White, 107 [13.3%]; Hispanic, 55 [18.2%]), but less likely to have a history of atrial fibrillation (White, 251 [31.2%]; Hispanic, 59 [19.5%]). Conclusions and Relevance: The results of this study suggest that the burden of SCA was similar in Hispanic and White individuals and lower in Asian individuals. The Asian and Hispanic populations had shared SCA risk factors, which were different from those of the White population. These findings underscore the need for an improved understanding of race/ethnicity-specific differences in SCA risk.
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Muerte Súbita Cardíaca/etnología , Muerte Súbita Cardíaca/epidemiología , Etnicidad/estadística & datos numéricos , Grupos Raciales/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/estadística & datos numéricos , Población Negra/estadística & datos numéricos , California/epidemiología , Costo de Enfermedad , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Población Blanca/estadística & datos numéricosRESUMEN
OBJECTIVES: The purpose of this study was to evaluate the potential impact of the coronavirus disease-2019 (COVID-19) pandemic on out-of-hospital cardiac arrest (OHCA) responses and outcomes in 2 U.S. communities with relatively low infection rates. BACKGROUND: Studies in areas with high COVID-19 infection rates indicate that the pandemic has had direct and indirect effects on community responses to OHCA and negative impacts on survival. Data from areas with lower infection rates are lacking. METHODS: Cases of OHCA in Multnomah County, Oregon, and Ventura County, California, with attempted resuscitation by emergency medical services (EMS) from March 1 to May 31, 2020, and from March 1 to May 31, 2019, were evaluated. RESULTS: In a comparison of 231 OHCA in 2019 to 278 in 2020, the proportion of cases receiving bystander cardiopulmonary resuscitation (CPR) was lower in 2020 (61% to 51%, respectively; p = 0.02), and bystander use of automated external defibrillators (AEDs) declined (5% to 1%, respectively; p = 0.02). EMS response time increased (6.6 ± 2.0 min to 7.6 ± 3.0 min, respectively; p < 0.001), and fewer OHCA cases survived to hospital discharge (14.7% to 7.9%, respectively; p = 0.02). Incidence rates did not change significantly (p > 0.07), and coronavirus infection rates were low (Multnomah County, 143/100,000; Ventura County, 127/100,000 as of May 31) compared to rates of â¼1,600 to 3,000/100,000 in the New York City region at that time. CONCLUSIONS: The community response to OHCA was altered from March to May 2020, with less bystander CPR, delays in EMS response time, and reduced survival from OHCA. These results highlight the pandemic's indirect negative impact on OHCA, even in communities with relatively low incidence of COVID-19 infection, and point to potential opportunities for countering the impact.
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Reanimación Cardiopulmonar/tendencias , Servicios Médicos de Urgencia/tendencias , Paro Cardíaco Extrahospitalario/terapia , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/epidemiología , California/epidemiología , Desfibriladores , Cardioversión Eléctrica/tendencias , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oregon/epidemiología , Paro Cardíaco Extrahospitalario/epidemiología , Paro Cardíaco Extrahospitalario/mortalidad , SARS-CoV-2 , Tasa de Supervivencia/tendencias , Factores de Tiempo , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: The ECG is a critical diagnostic tool for the management of immediate sudden cardiac arrest (SCA) survivors, but can be altered as a consequence of the SCA event. A limited number of studies report that electrical remodeling post SCA is due to prolonged myocardial repolarization, but a better understanding of this phenomenon is needed. AIM: To identify specific ECG abnormalities that follow SCA in immediate survivors. METHODS: SCA survivors with a pre-arrest ECG and an ECG obtained within 48â¯h post-SCA were prospectively collected in the Oregon Sudden Unexpected Death Study (Portland metro region) from 2002-2015. Ventricular depolarization and repolarization measurements were compared between pre-arrest and post-arrest ECGs using paired t-tests and assessed for association with survival using unpaired t-tests and Pearson's chi-square tests. RESULTS: A pre-arrest ECG and post-arrest ECG were available for 297 SCA cases (67.8⯱â¯13.4 years; 65.3% male). From the pre- to post-arrest setting, there was a significant mean increase in QRS (21â¯ms, pâ¯<â¯0.001) and QTc (35â¯ms, pâ¯<â¯0.001) in each SCA case, while there was no significant change in the JTc (4â¯ms, pâ¯=â¯0.361). Post-arrest QRS duration was significantly shorter in cases who survived to hospital discharge compared with those who did not survive (mean QRSD 115⯱â¯29â¯ms vs 127⯱â¯34â¯ms; pâ¯=â¯0.006). CONCLUSIONS: Contrary to expectations, electrical remodeling of the ECG due to SCA occurs due to prolongation of ventricular depolarization (QRSD), and not repolarization (JTc). Prolonged QRSD may also assist with prognostication and warrants further evaluation.
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Muerte Súbita Cardíaca , Electrocardiografía , Muerte Súbita Cardíaca/etiología , Femenino , Humanos , Masculino , Oregon , Factores de Riesgo , SobrevivientesRESUMEN
MicroRNA (miRNA) expression is tightly regulated by several mechanisms, including transcription and cleavage of the miRNA precursor RNAs, to generate a mature miRNA, which is thought to be directly correlated with activity. MiR-34 is a tumour-suppressor miRNA important in cell survival, that is transcriptionally upregulated by p53 in response to DNA damage. Here, we show for the first time that there is a pool of mature miR-34 in cells that lacks a 5'-phosphate and is inactive. Following exposure to a DNA-damaging stimulus, the inactive pool of miR-34 is rapidly activated through 5'-end phosphorylation in an ATM- and Clp1-dependent manner, enabling loading into Ago2. Importantly, this mechanism of miR-34 activation occurs faster than, and independently of, de novo p53-mediated transcription and processing. Our study reveals a novel mechanism of rapid miRNA activation in response to environmental stimuli occurring at the mature miRNA level.
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Daño del ADN/genética , MicroARNs/genética , Proteínas Argonautas/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular , Regulación de la Expresión Génica , Humanos , MicroARNs/metabolismo , Proteínas Nucleares , Fosforilación , Fosfotransferasas , Factores de Transcripción , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
We studied 10 Mennonite patients who carry the c.6200C>A missense mutation (p.A2067D) in the ATM gene, all of whom exhibited a phenotypic variant of ataxia-telangiectasia (A-T) that is characterized by early-onset dystonia and late-onset mild ataxia, as previously described. This report provides the pathogenetic evidence for this mutation on cellular functions. Several patients have developed cancer and subsequently experienced life-threatening adverse reactions to radiation (radiotoxicity) and/or chemotherapy. As the c.6200C>A mutation is, thus far, unique to the Mennonite population and is always associated with the same haplotype or haplovariant, it was important to rule out any possible confounding DNA variant on the same haplotype. Lymphoblastoid cells derived from Mennonite patients expressed small amounts of ATM protein, which had no autophosphorylation activity at ATM Ser1981, and trace-to-absent transphosphorylation of downstream ATM targets. A-T lymphoblastoid cells stably transfected with ATM cDNA which had been mutated for c.6200C>A did not show a detectable amount of ATM protein. The same stable cell line with mutated ATM cDNA also showed a trace-to-absent transphosphorylation of downstream ATM targets SMC1pSer966 and KAP1pSer824. From these results, we conclude that c.6200A is the disease-causing ATM mutation on this haplotype. The presence of at least trace amounts of ATM kinase activity on some immunoblots may account for the late-onset, mild ataxia of these patients. The cause of the dystonia remains unclear. Because this dystonia-ataxia phenotype is often encountered in the Mennonite population in association with cancer and adverse reactions to chemotherapy, an early diagnosis is important.
RESUMEN
ATM plays a critical role in cellular responses to DNA double-strand breaks (DSBs). We describe a new ATM-mediated DSB-induced DNA damage response pathway involving microRNA (miRNA): irradiation (IR)-induced DSBs activate ATM, which leads to the downregulation of miR-335, a miRNA that targets CtIP, which is an important trigger of DNA end resection in homologous recombination repair (HRR). We demonstrate that CREB is responsible for a large portion of miR-335 expression by binding to the promoter region of miR-335. CREB binding is greatly reduced after IR, corroborating with previous studies that IR-activated ATM phosphorylates CREB to reduce its transcription activity. Overexpression of miR-335 in HeLa cells resulted in reduced CtIP levels and post-IR colony survival and BRCA1 foci formation. Further, in two patient-derived lymphoblastoid cell lines with decreased post-IR colony survival, a "radiosensitive" phenotype, we demonstrated elevated miR-335 expression, reduced CtIP levels, and reduced BRCA1 foci formation. Colony survival, BRCA1 foci, and CtIP levels were partially rescued by miRNA antisense AMO-miR-335 treatment. Taken together, these findings strongly suggest that an ATM-dependent CREB-miR-335-CtIP axis influences the selection of HRR for repair of certain DSB lesions.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , MicroARNs/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinasas/genética , Reparación del ADN por Recombinación/genética , Proteínas Supresoras de Tumor/genética , Proteínas de la Ataxia Telangiectasia Mutada , Proteína BRCA1/genética , Proteínas de Ciclo Celular/metabolismo , Roturas del ADN de Doble Cadena/efectos de los fármacos , Daño del ADN/efectos de la radiación , Reparación del ADN/efectos de la radiación , Proteínas de Unión al ADN/metabolismo , Regulación hacia Abajo/efectos de la radiación , Endodesoxirribonucleasas , Expresión Génica/efectos de la radiación , Células HeLa , Humanos , MicroARNs/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Reparación del ADN por Recombinación/efectos de la radiación , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Ataxia telangiectasia is a devastating neurodegenerative disease caused primarily by loss of function mutations in ATM, a hierarchical DNA repair gene and tumour suppressor. So far, murine models of ataxia telangiectasia have failed to accurately recapitulate many aspects of the disease, most notably, the progressive cerebellar ataxia. Here we present a model of human ataxia telangiectasia using induced pluripotent stem cells, and show that small molecule read-through compounds, designed to induce read-through of mRNA around premature termination codons, restore ATM activity and improve the response to DNA damage. This platform allows for efficient screening of novel compounds, identification of target and off-target effects, and preclinical testing on relevant cell types for the pathogenic dissection and treatment of ataxia telangiectasia.
Asunto(s)
Ataxia Telangiectasia/patología , Células Madre Pluripotentes Inducidas/patología , Neuronas/patología , Bibliotecas de Moléculas Pequeñas/farmacología , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular , Reprogramación Celular/efectos de los fármacos , Reprogramación Celular/genética , Daño del ADN , Reparación del ADN/efectos de los fármacos , Reparación del ADN/efectos de la radiación , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/efectos de la radiación , Histonas/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/efectos de la radiación , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Células-Madre Neurales/efectos de la radiación , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/efectos de la radiación , Fenotipo , Fosforilación/efectos de los fármacos , Fosforilación/efectos de la radiación , Radiación IonizanteRESUMEN
In an effort to explore the possible causes of human radiosensitivity and identify more rapid assays for cellular radiosensitivity, we interrogated a set of assays that evaluate cellular functions involved in recognition and repair of DNA double-strand breaks: (1) neutral comet assay, (2) radiation-induced γ-H2AX focus formation, (3) the temporal kinetics of structural maintenance of chromosomes 1 phosphorylation, (4) intra-S-phase checkpoint integrity, and (5) mitochondrial respiration. We characterized a unique panel of 19 "radiosensitive" human lymphoblastoid cell lines from individuals with undiagnosed diseases suggestive of a DNA repair disorder. Radiosensitivity was defined by reduced cellular survival using a clonogenic survival assay. Each assay identified cell lines with defects in DNA damage response functions. The highest concordance rate observed, 89% (17/19), was between an abnormal neutral comet assay and reduced survival by the colony survival assay. Our data also suggested that the neutral comet assay would be a more rapid surrogate for analyzing DNA repair/processing disorders.